Methods for regulating transcription factors

Abstract

beta -sheet mimetics and methods relating to the same are disclosed. The beta -sheet mimetics have utility as protease and kinase inhibitors, as well as inhibitors of transcription factors and protein-protein binding interactions. Methods of the invention include administration of a beta -sheet mimetic, or use of the same for the manufacture of a medicament for treatment of a variety of conditions associated with the targeted protease, kinase, transcription factor and/or protein-protein binding interaction.

What is claimed is: 
     
       1. A method for inhibiting a transcription factor, comprising administering to an animal in need thereof an effective amount of a compound having the structure: ##STR860## or a pharmaceutically acceptable salt thereof, wherein C is --(CH 2 ) 0-3  --;   F is an optional carbonyl moiety;   R 1  and R 4  are independently selected from amino acid side chain moieties and derivatives thereof;   R 2  represents one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2  taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;   R 3  is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from --(CH 2 ) 1-2  --, --O-- and --S--;   Y and Z represent the remainder of the molecule; and   any two adjacent CH groups of the bicyclic ring may form a double bond.   
     
     
       2. The method of claim 1 wherein the ability of the transcription factor to bind DNA is controlled by reduction of a cysteine residue by a cellular oxidoreductase. 
     
     
       3. The method of claim 1 wherein the transcription factor is selected from NF-κB, AP-1, Myb, GRE, STAT-1 through -6, NFAT, IRF-1 and MAF. 
     
     
       4. The method of claim 1 wherein the transcription factor is NF-κB. 
     
     
       5. The method of claim 1 wherein the transcription factor is AP-1. 
     
     
       6. The method of claim 2 wherein the cellular oxidoreductase is ref-1. 
     
     
       7. The method of claim 1 wherein the warm-blooded animal has been diagnosed with, or is at risk of developing, a condition selected from Crohn's disease, asthma, rheumatoid arthritis, ischemia-reperfusion injury, GVHD, ALS, Alzheimer's disease, allograft rejection, adult T-cell leukemia, cancer and inflammatory bowel disease. 
     
     
       8. The method of claim 1 wherein the compound has the structure: ##STR861## 
     
     
       9. The method of claim 8 wherein the compound has the structure: 
     
     
       10. The method of claim 8 wherein the compound has the structure: 
     
     
       11. The method of claim 1 wherein the compound has the structure: 
     
     
       12. The method of claim 11 wherein the compound has the structure: 
     
     
       13. The method of claim 11 wherein the compound has the structure: 
     
     
       14. The method of claim 11 wherein the compound has the structure: 
     
     
       15. The method of claim 1 wherein the compound has the structure: 
     
     
       16. The method of claim 15 wherein the compound has the structure: 
     
     
       17. The method of claim 15 wherein the compound has the structure: 
     
     
       18. The method of claim 1 wherein Z is an amino acid side chain moiety or derivative thereof. 
     
     
       19. The method of claim 1 wherein Z is an unsubstituted or substituted lower chain alkyl, lower chain aryl or lower chain aralkyl moiety. 
     
     
       20. The method of claim 1 wherein Z is an unsubstituted or substituted phenyl or benzyl. 
     
     
       21. The method of claim 1 wherein Z is a mono-substituted phenyl or benzyl. 
     
     
       22. The method of claim 1 wherein F is present. 
     
     
       23. The method of claims 1 wherein F is absent. 
     
     
       24. The method of claim 1 wherein F--Y, taken together, is --C(═O)H, --C(═O)OH, --C(═O)OR, --C(═O)NHR, --C(═O)CH 2  X, --CH(OH)CH═CHC(═O)R, --CH(OH)CH═CHC(═O)OR, --C(═O)CH═CHC(═O)R, --C(═O)CH═CHC(═O)OR, --CH(OH)C.tbd.CC(═O)R, --CH(OH)C.tbd.CC(═O)OR, --CH(OH)CH═CHC(═O)NHR, --CH(OH)CH═CHC(═O)NRR, --C(═O)CH═CHC(═O)NHR, --C(═O)CH═CHC(═O)NRR, --CH(OH)C.tbd.CC(═O)NHR or --CH(OH)C.tbd.CC(═O)NRR, wherein each occurrence of R is independently selected from a straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated lower chain alkyl, aryl or aralkyl moiety, and X is Cl, F, Br or I. 
     
     
       25. The method of claim 22 wherein Y is an amino acid. 
     
     
       26. The method of claim 1 wherein R 2  is hydrogen or a lower chain alkyl. 
     
     
       27. The method of claim 1 wherein R 2  is hydrogen. 
     
     
       28. The method of claim 1 wherein R 2  is methyl. 
     
     
       29. The method of claim 1 wherein R 3  is an amino acid side chain moiety or derivative thereof. 
     
     
       30. The method of claim 1 wherein R 3  is hydrogen or methyl. 
     
     
       31. The method of claim 1 wherein R 3  is hydrogen. 
     
     
       32. The method of claim 1 wherein the compound is administered to the animal for treatment of inflammation. 
     
     
       33. The method of claim 32 wherein the inflammation is transplantation rejection, arthritis, rheumatoid arthritis, infection, dermatosis, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and autoimmune disease. 
     
     
       34. The method of claim 32 wherein the inflammation is associated with psoriasis or restenosis.